A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors.
A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors.
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发表时间：
2002-10
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通讯作者：
J. Posey;M. Khazaeli;M. Bookman;A. Nowrouzi;W. Grizzle;J. Thornton;D. Carey;J. Lorenz;A. Sing;C. Siegall;A. Lobuglio;M. Saleh
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作者：
J. Posey;M. Khazaeli;M. Bookman;A. Nowrouzi;W. Grizzle;J. Thornton;D. Carey;J. Lorenz;A. Sing;C. Siegall;A. Lobuglio;M. Saleh
研究目的：探讨单链免疫毒素SGN-10（或BR 96 sFv-PE 40）的最大耐受剂量和毒性。SGN-10由编码假单胞菌外毒素（PE 40）的易位和ADP-核糖基化结构域与BR 96单克隆抗体的可变重链（V（H））和可变轻链（V（L））区的融合基因产物组成。该抗体对多种癌上表达的刘易斯（Y）（Le（Y））相关碳水化合物抗原具有特异性。实验设计一项I期剂量递增研究共招募了46例Le（Y）阳性转移性癌患者，队列中有3 - 6例患者接受SGN-10，剂量范围为0. 024 - 0. 962 mg/m2，在第1、4、8和11天给药，随后停药2周，并接受第二个周期的治疗。还测定了SGN-10的药代动力学和人抗体应答。结果SGN-10的最大耐受剂量为0.641mg/m2，胃肠道毒性为剂量限制性毒性。在8名患者中进行的0.641 mg/m2剂量的药代动力学研究显示，t（[1/2]）为2.5 +/- 0.3 h，C（max）为389 +/- 112 ng/ml。药效学分析表明，药物在第11天快速清除，与大多数患者的抗毒素人抗毒素抗体（HATA）反应相关。在接受≥ 0.384 mg/m2剂量治疗的患者中观察到与中度血管渗漏综合征一致的体征，特别是短暂性低白蛋白血症。在8周的评估中没有观察到完全或部分肿瘤缓解，尽管31%的患者病情稳定。结论SGN-10每周2次给药2周的最大耐受剂量为0.641 mg/m2，胃肠道毒性为剂量限制性毒性。毒素部分的免疫原性限制了SGN-10在治疗第11天循环的能力。正在进行研究，以评价改善毒性和抑制抗SGN-10免疫应答发展的策略。
PURPOSE Our purpose in the study was to establish the maximum tolerated dose and toxicity profile of SGN-10 (or BR96 sFv-PE40), a single-chain immunotoxin. SGN-10 is composed of the fused gene products encoding the translocating and ADP-ribosylating domains of Pseudomonas exotoxin (PE40) and the variable heavy (V(H)) and variable light (V(L)) regions of BR96 monoclonal antibody. This antibody is specific for a Lewis(Y) (Le(Y))-related carbohydrate antigen expressed on multiple carcinomas. EXPERIMENTAL DESIGN A total of 46 patients with Le(Y)-positive metastatic carcinoma were enrolled in a Phase I dose-escalation study in cohorts of three to six patients who received SGN-10 at doses ranging from 0.024 to 0.962 mg/m(2), administered on days 1, 4, 8, and 11, followed by 2 weeks of rest and a second cycle of therapy. Pharmacokinetics and human antibody response to SGN-10 were also determined. RESULTS The maximum tolerated dose of SGN-10 was 0.641 mg/m(2) with gastrointestinal dose-limiting toxicity. Pharmacokinetic studies performed in eight patients at the 0.641-mg/m(2) dose revealed a t([1/2]) of 2.5 +/- 0.3 h and a C(max) of 389 +/- 112 ng/ml. Pharmacodynamic analyses demonstrated a rapid clearance of the drug by day 11 associated with an antitoxin human antitoxin antibody (HATA) response in most patients. Signs consistent with a modest vascular leak syndrome, specifically, transient hypoalbuminemia, were observed in patients treated with doses of > or =0.384 mg/m(2). No complete or partial tumor responses were observed at an 8-week evaluation, although 31% of patients had stable disease. CONCLUSIONS The maximal tolerated dose of SGN-10 given twice weekly for 2 weeks is 0.641 mg/m(2) with gastrointestinal dose-limiting toxicity. The immunogenicity of the toxin moiety limits the ability of SGN-10 to circulate by day 11 of therapy. Studies are ongoing to evaluate strategies to ameliorate toxicities and to inhibit the development of the anti-SGN-10 immune response.